Medical devices having improved mechanical performance

ABSTRACT

According to an aspect of the present invention, implantable or insertable medical devices are provided that contain at least one covalently crosslinked polymeric region, which contains at least one block copolymer comprising at least one low Tg block and at least one high Tg block.

STATEMENT OF RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/840,309, filed Aug. 25, 2006, entitled“Polymeric/Ceramic Composite Materials for Use in Medical Devices”,which is incorporated by reference in its entirety herein.

FIELD OF THE INVENTION

The present invention relates generally to medical devices, and moreparticularly to implantable or insertable medical devices.

BACKGROUND OF THE INVENTION

Thermoplastic elastomers are elastomeric (i.e., reversibly deformable)polymers that form physical crosslinks which are reversible, forexample, by dissolving or melting the polymer. Triblock copolymershaving an elastomeric low glass transition temperature (Tg) midblock andhard elevated Tg endblocks are common examples of thermoplasticelastomers. As is well known, such copolymers tend to phase separate,with the elastomeric blocks aggregating to form elastomeric phasedomains and the hard blocks aggregating to form hard phase domains.Without wishing to be bound by theory, it is believed that because eachelastomeric block has a hard block at each end, and because differenthard blocks within the same triblock copolymer are capable of occupyingtwo different hard phase domains, the hard phase domains becomephysically crosslinked to one another via the soft blocks.

Examples of such triblock copolymers arepoly(styrene-b-isoprene-b-styrene) (SIS),poly(styrene-b-butadiene-b-polystyrene) (SBS),poly(styrene-b-ethylene/butylene-b-styrene) (SEBS), andpoly(styrene-b-isobutylene-b-styrene) (SIBS). Taking SIBS as a specificexample, these polymers have proven valuable as drug release polymers inimplantable or insertable drug-releasing medical devices such asdrug-eluting coronary stents. In addition to their drug releasecharacteristics, SIBS copolymers have been shown to have excellentbiostability and biocompatibility, particularly within the vasculature.Moreover, they have excellent mechanical properties for coronary stentapplications, including good elasticity and high tensile strength. As aresult of their mechanical properties, these polymers are able toundergo crimping and to expand as the stent is expanded.

Despite the desirable qualities of these and other thermoplasticelastomers, there are situations where it would be desirable to improveone or more mechanical properties of these materials, including, forexample, one or more of strength, elongation at break, and abrasionresistance, among others.

SUMMARY OF THE INVENTION

According to an aspect of the present invention, implantable orinsertable medical devices are provided that contain at least onecovalently crosslinked polymeric region, which contains at least oneblock copolymer. The at least one block copolymer further contains atleast one low Tg block and at least one high Tg block.

An advantage of the present invention is that that one or moremechanical properties of various multiblock thermoplastic elastomers maybe improved for a given medical application.

These and other aspects, embodiments and advantages of the presentinvention will become immediately apparent to those of ordinary skill inthe art upon review of the Detailed Description and Claims to follow.

DETAILED DESCRIPTION OF THE INVENTION

A more complete understanding of the present invention is available byreference to the following detailed description of numerous aspects andembodiments of the invention. The detailed description of the inventionwhich follows is intended to illustrate but not limit the invention.

According to an aspect of the present invention, implantable orinsertable medical devices are provided that contain at least onecovalently crosslinked polymeric region, which contains at least oneblock copolymer. The at least one block copolymer further contains atleast one low Tg block and at least one high Tg block.

Medical devices benefiting from the present invention vary widely andinclude a variety of medical devices, which are implanted or insertedinto a subject, either for procedural uses or as implants.

Examples of medical devices which may utilize covalently crosslinkedpolymeric regions in accordance with the invention include prostheticdevices, for example, load bearing joints, such as knee, hip, and spinaldisk replacements. There is a general need to reduce oxidation and wearresistance in such implants as well.

Further examples of medical devices which may utilize covalentlycrosslinked polymeric regions in accordance with the invention includethose requiring coatings that are wear resistant and have relatively lowcoefficients of friction. Such devices include those that transmitand/or contact tissue such as needles, sutures, guidewires, catheters,balloons, and balloon catheters. In the specific example of a balloon,durable coatings with good wear resistance to tissue are highlydesirable. Moreover, such coatings may also reduce withdrawal resistancewhen removing the balloon from dilated tissue or from a deployed stent,especially when using non-compliant balloons that do not fully deflateor balloons that have a tendency to creep after multipleinflation/deflation cycles (i.e., they do not deflate back to theiroriginal size). Such coatings could also allow balloons to re-crossstent lesions more easily. With respect to catheters, these devices mayhave the potential to be cut during placement, which can lead to failureof the catheter. Such coatings could increase the tear resistance andthe abrasion resistance of the catheter.

Further examples of medical devices which may utilize covalentlycrosslinked polymeric regions in accordance with the invention includeurethral slings, hernia “meshes”, artificial ligaments, vascular grafts,stent grafts, stents (including coronary artery stents, peripheralvascular stents such as cerebral stents, urethral stents, ureteralstents, biliary stents, tracheal stents, gastrointestinal stents andesophageal stents), embolization devices including cerebral aneurysmfiller coils (including Guglilmi detachable coils and metal coils),suture anchors, anastomosis clips and rings, valves including heartvalves and vascular valves, ventricular assist devices, lead coatingsincluding coatings for pacemaker leads, shunts, cochlear implants,dialysis ports, tissue staples and ligating clips at surgical sites,cannulae, metal wire ligatures, orthopedic prosthesis such as bonegrafts, bone plates, dental implants, dental root sealer, whiteningstrips, embolic agents, hermetic sealants, active bandages, belly bands,gastric balloons, and obesity devices.

Hence, in some embodiments, the polymeric regions of the presentinvention correspond to an entire medical device. In other embodiments,the polymeric regions correspond to one or more portions of a medicaldevice. For instance, the polymeric regions can be in the form ofmedical device components, in the form of one or more fibers which areincorporated into a medical device, in the form of one or more polymericlayers formed over all or only a portion of an underlying substrate, andso forth. Materials for use as underlying medical device substratesinclude ceramic, metallic and polymeric substrates. The substratematerial can also be a carbon- or silicon-based material, among others.Layers can be provided over an underlying substrate at a variety oflocations and in a variety of shapes (e.g., in the form of a series ofrectangles, stripes, or any other continuous or non-continuous pattern).As used herein a “layer” of a given material is a region of thatmaterial whose thickness is small compared to both its length and width.As used herein a layer need not be planar, for example, taking on thecontours of an underlying substrate. Layers can be discontinuous (e.g.,patterned).

As used herein, a “polymeric region” is a region (e.g., an entiredevice, a device component, a device coating layer, etc.) that containspolymers, for example, from 50 wt % or less to 75 wt % to 90 wt % to 95wt % to 97.5 wt % to 99 wt % or more polymers.

As used herein, “polymers” are molecules containing multiple copies(e.g., from 2 to 5 to 10 to 25 to 50 to 100 to 250 to 500 to 1000 ormore copies) of one or more constitutional units, commonly referred toas monomers.

Polymers may take on a number of configurations, which may be selected,for example, from cyclic, linear and branched configurations, amongothers. Branched configurations include star-shaped configurations(e.g., configurations in which three or more chains emanate from asingle branch point), comb configurations (e.g., configurations having amain chain and a plurality of side chains), dendritic configurations(e.g., arborescent and hyperbranched polymers), and so forth.

As used herein, “homopolymers” are polymers that contain multiple copiesof a single constitutional unit. “Copolymers” are polymers that containmultiple copies of at least two dissimilar constitutional units,examples of which include random, statistical, gradient, periodic (e.g.,alternating) and block copolymers.

As used herein, “block copolymers” are copolymers that contain two ormore polymer blocks that differ in composition, for instance, because aconstitutional unit (i.e., a monomer) is found in one polymer block thatis not found in another polymer block. As used herein, a “polymer block”is a grouping of constitutional units (e.g., 5 to 10 to 25 to 50 to 100to 250 to 500 to 1000 or more units). Blocks can be branched orunbranched. Blocks can contain a single type of constitutional unit(also referred to herein as “homopolymeric blocks”) or multiple types ofconstitutional units (also referred to herein as “copolymeric blocks”)which may be present, for example, in a random, statistical, gradient,or periodic (e.g., alternating) distribution.

As used herein, a “chain” is a linear polymer or a portion thereof, forexample, a linear block.

As used herein, a “low Tg polymer block” is one that displays a Tg thatis below body temperature, more typically from 35° C. to 20° C. to 0° C.to −25° C. to −50° C. or below. Conversely, as used herein, an elevatedor “high Tg polymer block” is one that displays a Tg that is above bodytemperature, more typically from 40° C. to 50° C. to 75° C. to 100° C.or above. Tg can be measured by differential scanning calorimetry (DSC).

Block copolymer configurations may vary widely and include, for example,the following configurations, among others, which comprise two more highTg polymer chains (designated “H”) and one or more low Tg polymer chains(designated “L”): (a) block copolymers having alternating chains of thetype HLH, (HL)_(m), L(HL)_(m) and H(LH)_(m) where m is a positive wholenumber of 2 or more, (b) multiarm (including star) copolymers such asX(LH)_(n), where n is a positive whole number of 2 or more, and X is ahub species (e.g., an initiator molecule residue, a linking residue,etc.), and (c) comb copolymers having an L chain backbone and multiple Hside chains.

Specific examples of low Tg polymer blocks include homopolymer andcopolymer blocks containing one or more of the following (listed alongwith published Tg's for homopolymers of the same): (1) alkene monomersincluding ethylene, propylene (Tg −8 to −13° C.), isobutylene (Tg −73°C.), 1-butene (Tg −24° C.), 4-methyl pentene (Tg 29° C.), 1-octene (Tg−63° C.) and other α-olefins, dienes such as 1,3-butadiene,2-methyl-1,3-butadiene (isoprene), 2,3-dimethyl-1,3-butadiene,2-ethyl-1,3-butadiene, 1,3-pentadiene, 2-methyl-1,3-pentadiene,4-butyl-1,3-pentadiene, 2,3-dibutyl-1,3-pentadiene,2-ethyl-1,3-pentadiene, 1,3-hexadiene, 1,3-octadiene, and3-butyl-1,3-octadiene; (2) acrylic monomers including: (a) alkylacrylates such as methyl acrylate (Tg 10° C.), ethyl acrylate (Tg −24°C.), propyl acrylate, isopropyl acrylate (Tg −11° C., isotactic), butylacrylate (Tg −54° C.), sec-butyl acrylate (Tg −26° C.), isobutylacrylate (Tg −24° C.), cyclohexyl acrylate (Tg 19° C.), 2-ethylhexylacrylate (Tg −50° C.), dodecyl acrylate (Tg −3° C.) and hexadecylacrylate (Tg 35° C.), (b) arylalkyl acrylates such as benzyl acrylate(Tg 6° C.), (c) alkoxyalkyl acrylates such as 2-ethoxyethyl acrylate (Tg−50° C.) and 2-methoxyethyl acrylate (Tg −50° C.), (d) halo-alkylacrylates such as 2,2,2-trifluoroethyl acrylate (Tg −10° C.) and (e)cyano-alkyl acrylates such as 2-cyanoethyl acrylate (Tg 4° C.); (3)methacrylic monomers including (a) alkyl methacrylates such as butylmethacrylate (Tg 20° C.), hexyl methacrylate (Tg −5° C.), 2-ethylhexylmethacrylate (Tg −10° C.), octyl methacrylate (Tg −20° C.), dodecylmethacrylate (Tg −65° C.), hexadecyl methacrylate (Tg 15° C.) andoctadecyl methacrylate (Tg −100° C.) and (b) aminoalkyl methacrylatessuch as diethylaminoethyl methacrylate (Tg 20° C.) and2-tert-butyl-aminoethyl methacrylate (Tg 33° C.); (4) vinyl ethermonomers including (a) alkyl vinyl ethers such as methyl vinyl ether (Tg−31° C.), ethyl vinyl ether (Tg −43° C.), propyl vinyl ether (Tg −49°C.), butyl vinyl ether (Tg −55° C.), isobutyl vinyl ether (Tg −19° C.),2-ethylhexyl vinyl ether (Tg −66° C.) and dodecyl vinyl ether (Tg −62°C.); (5) cyclic ether monomers include tetrahydrofuran (Tg −84° C.),trimethylene oxide (Tg −78° C.), ethylene oxide (Tg −66° C.), propyleneoxide (Tg −75° C.), methyl glycidyl ether (Tg −62° C.), butyl glycidylether (Tg −79° C.), allyl glycidyl ether (Tg −78° C.), epibromohydrin(Tg −14° C.), epichlorohydrin (Tg −22° C.), 1,2-epoxybutane (Tg −70°C.), 1,2-epoxyoctane (Tg −67° C.) and 1,2-epoxydecane (Tg −70° C.); (6)ester monomers (other than the above acrylates and methacrylates)including ethylene malonate (Tg −29° C.), vinyl acetate (Tg 30° C.), andvinyl propionate (Tg 10° C.); (7) halogenated alkene monomers includingvinylidene chloride (Tg −18° C.), vinylidene fluoride (Tg −40° C.),cis-chlorobutadiene (Tg −20° C.), and trans-chlorobutadiene (Tg −40°C.); and (8) siloxane monomers including dimethylsiloxane (Tg −127° C.),diethylsiloxane, methylethylsiloxane, methylphenylsiloxane (Tg −86° C.),and diphenylsiloxane.

Specific examples of high Tg polymer blocks include homopolymer andcopolymer blocks containing one or more of the following: (1) vinylaromatic monomers including (a) unsubstituted vinyl aromatics, such asstyrene (Tg 100° C.) and 2-vinyl naphthalene (Tg 151° C.), (b) vinylsubstituted aromatics such as alpha-methyl styrene, and (c)ring-substituted vinyl aromatics including ring-hydroxylated vinylaromatics such as 4-hydroxystyrene (Tg 174° C.), ring-alkylated vinylaromatics such as 3-methylstyrene (Tg 97° C.), 4-methylstyrene (Tg 97°C.), 2,4-dimethylstyrene (Tg 112° C.), 2,5-dimethylstyrene (Tg 143° C.),3,5-dimethylstyrene (Tg 104° C.), 2,4,6-trimethylstyrene (Tg 162° C.),and 4-tert-butylstyrene (Tg 127° C.), ring-alkoxylated vinyl aromatics,such as 4-methoxystyrene (Tg 113° C.) and 4-ethoxystyrene (Tg 86° C.),ring-halogenated vinyl aromatics such as 2-chlorostyrene (Tg 119° C.),3-chlorostyrene (Tg 90° C.), 4-chlorostyrene (Tg 110° C.),2,6-dichlorostyrene (Tg 167° C.), 4-bromostyrene (Tg 118° C.) and4-fluorostyrene (Tg 95° C.), ring-ester-substituted vinyl aromatics suchas 4-acetoxystyrene (Tg 116° C.), ring-amino-substituted vinyl aromaticsincluding 4-amino styrene, ring-silyl-substituted styrenes such asp-dimethylethoxy siloxy styrene, unsubstituted and substituted vinylpyridines such as 2-vinyl pyridine (Tg 104° C.) and 4-vinyl pyridine (Tg142° C.), and other vinyl aromatic monomers such as vinyl carbazole (Tg227° C.) and vinyl ferrocene (Tg 189° C.); (2) other vinyl monomersincluding (a) vinyl esters such as vinyl benzoate (Tg 71° C.), vinyl4-tert-butyl benzoate (Tg 101° C.), vinyl cyclohexanoate (Tg 76° C.),vinyl pivalate (Tg 86° C.), vinyl trifluoroacetate (Tg 46° C.), vinylbutyral (Tg 49° C.), (b) vinyl amines, (c) vinyl halides such as vinylchloride (Tg 81° C.) and vinyl fluoride (Tg 40° C.), and (d) alkyl vinylethers such as tert-butyl vinyl ether (Tg 88° C.) and cyclohexyl vinylether (Tg 81° C.); (3) other aromatic monomers including acenaphthalene(Tg 214° C.) and indene (Tg 85° C.); (4) methacrylic monomers including(a) methacrylic acid anhydride (Tg 159° C.), (b) methacrylic acid esters(methacrylates) including (i) alkyl methacrylates such as methylmethacrylate (Tg 105-120° C.), ethyl methacrylate (Tg 65° C.), isopropylmethacrylate (Tg 81° C.), isobutyl methacrylate (Tg 53° C.), t-butylmethacrylate (Tg 118° C.) and cyclohexyl methacrylate (Tg 92° C.), (ii)aromatic methacrylates such as phenyl methacrylate (Tg 110° C.) andincluding aromatic alkyl methacrylates such as benzyl methacrylate (Tg54° C.), (iii) hydroxyalkyl methacrylates such as 2-hydroxyethylmethacrylate (Tg 57° C.) and 2-hydroxypropyl methacrylate (Tg 76° C.),(iv) additional methacrylates including isobornyl methacrylate (Tg 110°C.) and trimethylsilyl methacrylate (Tg 68° C.), and (c) othermethacrylic-acid derivatives including methacrylonitrile (Tg 120° C.);(5) acrylic monomers including (a) certain acrylic acid esters such astert-butyl acrylate (Tg 43-107° C.), hexyl acrylate (Tg 57° C.) andisobornyl acrylate (Tg 94° C.); and (b) other acrylic-acid derivativesincluding acrylonitrile (Tg 125° C.).

As used herein, a poly(vinyl aromatic) block is a block that containsmultiple copies of one or more types of vinyl aromatic monomers, apolyalkene block is a block that contains multiple copies of one or moretypes of alkene monomers, and so forth.

As noted above, the medical devices of the present invention contain atleast one covalently crosslinked polymeric region, which contains atleast one block copolymer. The at least one block copolymer furthercontains (a) at least one low Tg block and (b) at least one high Tgblock. For example, two or more high Tg blocks may be interconnectedthrough one or more low Tg blocks, among many other possibilities.

Covalent crosslinking has been shown to increase the strength andelongation of triblock copolymers. See, e.g., S. Sakurai et al.,“Mechanical properties ofpolystyrene-block-polybutadiene-block-polystyrene triblock copolymerscrosslinked in the disordered state,” Polymer 40 (1999) 2071-2076.Crosslinking is also expected to improve further mechanical propertiesincluding, for example, one or more of creep resistance, abrasionresistance and tear resistance, among others. Improvement in mechanicalproperties will improve the performance of various medical devices.

In some embodiments, one or more blocks within the block copolymeritself are sufficiently reactive to undergo crosslinking. In otherembodiments, the block copolymer is modified to render it sufficientlyreactive. In still other embodiments, reactive species are introducedduring the polymerization process to render the block copolymersufficiently reactive. In yet other embodiments, the block copolymer isblended with a supplemental reactive polymer, which is then crosslinked,thereby forming an interpenetrating network.

Polymers may be crosslinked in a variety of ways. For instance,crosslinking may be initiated by exposure to energy (e.g., theapplication of heat or ionizing or non-ionizing radiation such as e-beamradiation, gamma radiation, UV light, visible light, etc.) or a chemicalagent (e.g., moisture), or both. Crosslinking may progress with the aidof suitable chemical species, for example, catalysts (e.g., species thataid in completion of a chemical reaction without becoming part of thereaction product) and/or crosslinking agents (e.g., species which formbonds with other molecules and which become part of the crosslinkedpolymer network), among others.

As a first example, various polyalkenes, including polymers formed fromethylene and/or propylene, among others, can undergo crosslinking as aresult of the formation of radical species along their backbones.Radicals may form, for example, upon exposure to ionizing radiation(e.g., from high energy electrons, x-rays, gamma radiation, and soforth). Radicals may also form upon exposure to free-radical generatingspecies such as peroxides, peresters, and azo compounds, among others,with peroxides such as the following being commonly used:2,5-dimethyl-2,5-bis(t-butylperoxy)-3-hexyne (Lupersol 130, AtochemInc., Philadelphia, Pa.); 2,5-dimethyl-2,5-di-(t-butylperoxy)-hexane(Varox 130); t-butyl alpha-cumyl peroxide; di-butyl peroxide; t-butylhydroperoxide; benzoyl peroxide; dichlorobenzoyl peroxide; dicumylperoxide (Lupersol 101, Atochem Inc.); di-t-butyl peroxide; 2,5dimethyl-2,5-di(peroxy benzoate)-3-hexyne; 1,3-bis(t-butyl peroxyisopropyl)benzene; lauroyl peroxide; di-t-amyl peroxide;1,1-di-(t-butylperoxy)cyclohexane; 2,2-di-(t-butylperoxy)butane; and2,2-di-(t-amylperoxy)propane.

Once formed, radicals on two different chains may combine to form a bondbetween the chains. This reaction is may be enhanced when the polymer isin a mobile state, for example, in a melt state, which state may beestablished concurrently with radical formation, or subsequent toradical formation.

Based on these principles, polyalkene block copolymers (e.g., triblockcopolymers having high Tg endblocks and having low Tg centerblocks thatcontain ethylene, propylene or both, etc.) may be crosslinked byexposure to radiation or free-radical-forming compounds, for instance,while in the melt stage. Commercially available examples of blockcopolymers of this type include, for instance, KRATON G series polymersfrom Kraton Polymers, Houston Tex., USA, specifically SEBS, apoly(styrene-b-ethylene/butylene-b-styrene) triblock copolymer (e.g.,KRATON G 1650, 1651, 1652, 1654, 1657, etc.). As one specific example,such a copolymer may be heated in a mold (e.g., corresponding in shapeto the desired medical device or device component) to the melt stage andthen crosslinked, for example, by applying ionizing radiation or byincluding a free-radical generating species that is activated uponheating to the melt stage.

In addition to being reactive with one another, radicals created onpolymer chains are also reactive with various additional species,including multifunctional crosslinking species, such as those having oneor more sites of unsaturation (e.g., —HC═CH— or —C≡C—).

For example, in some embodiments of the invention, vinyl crosslinkingagents

may be added to enhance crosslinking between the radicalized blockcopolymers. For instance, alkenes such as HC═CH—(CH₂)_(n)—HC═CH, where nis an integer, for example, ranging from 0 to 20, may be used for thispurpose. In this regard, see, e.g., P. Bracco et al., infra, in whichultra high molecular weight polyethylene soaked in 1,7-octadiene, amongother species, is crosslinked upon exposure to electron beam radiation.Such radicals may also be generated by the introduction of free radicalgenerating compounds such as peroxides as noted above.

Other examples of multifunctional crosslinking agents include terminallyunsaturated, linear or branched, polymers, for example, polyalkenes(e.g., polyethylene, polybutylene, poly(ethylene-co-polybutylene),polyisbutylene, etc.), polyvinyl aromatics, polysiloxanes,polyacrylates, polymethacrylates, and so forth, which polymers maycontain, for example, from 2 to 5 to 10 to 25 to 50 to 100 or moremonomer units. Certain of these polymers (e.g., polyisbutylene andpolymethacrylates) are susceptible to chain scission upon exposure toradiation.

In this regard, compatibility between the crosslinking agents and theblock copolymers may be enhanced by using multifunctional crosslinkingagents that contain polymer blocks which have the same or similarmonomer composition as is found in the block copolymer to becrosslinked. For instance, SEBS may be crosslinked using terminallyunsaturated polyethylene, polybutylene, or polystyrene.

Polymer blocks that contain one or more types of diene monomer areparticularly amenable to crosslinking, including chemical basedcrosslinking (e.g., using free-radical generating species), energy basedcrosslinking (e.g., using ionizing or non-ionizing radiation) or both.Dienes for forming polymer blocks may be selected, for example, fromsuitable members of those described above, among others. Specificexamples of block copolymers include poly(styrene-b-isoprene-b-styrene)(SIS) and poly(styrene-b-butadiene-b-polystyrene) (SBS) triblockcopolymers, among others.

As a specific example, R. Basheer et al., “The radiation crosslinking ofblock copolymers of butadiene and styrene,” Die Makromolekulare Chemie,2003, Volume 183, Issue 9, 2141-2151 describe a process whereby blockcopolymers of butadiene and styrene are crosslinked by exposure to gammaradiation. Crosslinking of SBS and SIS by electron beam radiation isdescribed in H. Kanbara et al., “Measurement of crosslinking degree forelectron beam irradiated block copolymers,” Polymer Engineering andScience, 2004, Volume 34, Issue 8, pp. 691-694. As another specificexample, S. Sakurai et al., “Mechanical properties ofpolystyrene-block-polybutadiene-block-polystyrene triblock copolymerscrosslinked in the disordered state,” Polymer 40 (1999) 2071-2076demonstrated that SBS may be crosslinked using a peroxide agent,specifically 1,1-bis(tert-butylperoxy)-3,3,5-trimethylcyclohexane. As afurther specific example, C. Decker, et al., “High-speedphotocrosslinking of thermoplastic styrene-butadiene elastomers,”Journal of Applied Polymer Science, 2000, Volume 77, Issue 9, 1902-1912,report the crosslinking of SBS and SIS copolymers using an acylphosphineoxide photoinitiator and a trifunctional thiol crosslinking agent.Decker et al. also report the photocrosslinking of SBS upon UV exposurein the presence of an acylphosphine oxide photoinitiator and,optionally, a telechelic acrylate oligomer in Macromolecular Chemistryand Physics, “Photocrosslinking of functionalized rubbers, 7.Styrene-butadiene block copolymers,” 1999, Volume 200, Issue 2, Pages358-367.

In other embodiments, polymers are rendered crosslinkable by providingthem with readily crosslinkable groups, either during or subsequent topolymerization of the same. Crosslinkable groups may be provided at oneor more chain ends of the polymer, along the polymer backbone(s) of thepolymer, or a combination of both.

For example, silane compounds that have a combination of unsaturated andhydrolyzable groups may be grafted, for example, onto polyalkenes (e.g.,polymers containing ethylene and/or butylene) under free radicalgenerating conditions (e.g., in the presence of a suitable peroxide orin the presence of ionizing radiation). As a specific example, vinyltrimethoxysilane has been grafted to polyethylene using dicumyl peroxideas the grafting agent. Such polymers are moisture curable(crosslinkable). In particular, crosslinking may proceed upon exposureto water, which causes the alkoxy groups in the polymer to behydrolyzed, followed by condensation of neighboring hydroxyl groups toform the crosslinks containing —Si—O—Si— linkages. This process may bepromoted, for example, by steam autoclaving or through the use of asuitable catalyst, for example an organo-tin catalyst.

Using analogous processes, in accordance with the invention, blockcopolymers with polymer blocks containing, for example, ethylene,propylene or both, may be crosslinked with species having one or moresites of unsaturation and one or more hydrolysable silane groups.Specific examples of such silanes, among others, include species of theformula HC═CH—(CH₂)_(n)—Si—(OR)₃, where n is an integer, for example,ranging from 0 to 20, and R is selected from alkyl groups having 1 to 10carbon atoms and aryl groups having 6 to 10 carbon atoms.

As another example, crosslinking may be achieved by firsthydrosilylating an ethylene propylene diene monomer (EPDM) rubber with asilane compound, whereupon the silicon hydride bond (Si—H) reacts withthe pendant olefinic unsaturation found in the EPDM rubber. The silanealso preferably contains multiple alklysiloxy groups for subsequentcrosslinking reactions. An example of such a compound istris(trimethylsiloxy)silane available from Sigma-Aldrich and Gelest,Inc. Morrisville, Pa., USA (product # SIT8721.0).

It is also known to graft unsaturated acid anhydrides onto polymerchains, including those containing ethylene or propylene. For instance,it is known to graft of maleic anhydride onto polyalkene chains in thepresence of organic peroxides. Examples of peroxides are listed above.Maleation of polyalkene chains may be performed, for example, insolution or in the melt phase (e.g., by reactive extrusion, etc.), amongother processes.

Using analogous processes, block copolymers containing ethylene,propylene or both, may be maleated. Block copolymers of this type arecommercially available. For example, maleated SEBS is available fromKraton Polymers as Kraton FG series polymers (e.g., FG1901 or FG1924X).Such maleated polymers may then be crosslinked via multifunctionalcrosslinking species, each containing two or more groups that arereactive with the grafted anhydride groups, for example, amine groupsand/or hydroxyl groups, among others. Examples of such species includemultifunctional alcohols, multifunctional amines, linear or branchedpolyalkenes with terminal hydroxyl and/or amine groups, linear orbranched poly(vinyl aromatics) with terminal hydroxyl and/or aminegroups, and so forth.

After crosslinking, any residual maleic anhydride units can behydrolyzed to form carboxylates (carboxylic acid groups). These groupscan form hydrogen bonds which can also act as physical crosslinks.

Further information concerning crosslinking of polyalkenes may be found,for example, in P. Bracco et al., “Radiation-induced crosslinking ofUHMWPE in the presence of co-agents: chemical and mechanicalcharacterization,” Polymer 46 (2005) 10648-10657, G. Lewis, “Propertiesof crosslinked ultra-high-molecular-weight polyethylene,” Biomaterials22 (2001) 371-401, S. M. Kurtz et al., “Advances in the processing,sterilization, and crosslinking of ultra-high molecular weightpolyethylene for total joint arthroplasty,” Biomaterials 20 (1999)1659-1688, U.S. Pat. No. 4,036,719 to Lyons, U.S. Patent App. No.2005/0031813 to Cornette et al., U.S. Patent App. No. 2005/0218551 toHalahmi et al., and U.S. Patent App. No. 2004/0208841 to Salovey et al.,the disclosures of which are hereby incorporated by reference.

As another example, dienes can also be reacted with peroxy acids to formepoxy groups, which can be crosslinked by treatment with radiation. Onestudy, in which epoxidized natural rubber was crosslinked viairradiation, found that most of the crosslinking was due to epoxy groupring opening, and very little or no C—C crosslinking was observed. M CSenake Perera, “Radiation degradation of epoxidized natural rubberstudied by solid-state nuclear magnetic resonance and infraredspectroscopy,” Polymer International Volume 49, Issue 7, 2000, Pages691-698. If desired, the dienes may be partially hydrogenation prior toformation of epoxy groups, as described in U.S. Pat. No. 5,491,193 toErickson. For example, in Erickson, polymers are hydrogenated to producea partially hydrogenated polymer which has remaining about 0.1 to about5 milliequivalents per gram of polymer of residual aliphatic doublebonds. The partially hydrogenated polymer is contacted with a peroxyacid to form an epoxidized polymer, which has between 0.1 and about 5milliequivalents of epoxide per gram of polymer. The epoxidized polymeris then exposed to an amount of radiation (either ionizing ornon-ionizing) sufficient to crosslink the polymer.

In other embodiments, polydienes may be epoxidized to the desireddegree, followed by crosslinking and then hydrogenation to reduce/removeresidual unsaturation.

Other embodiments of the invention involve the incorporation of reactivespecies in conjunction with the polymerization process.

In this regard, cationic polymerization of unsaturated monomers,including alkenes such as isobutylene, butadiene, isoprene,methylbutene, and 2-methylpentene, among others, or vinyl aromaticmonomers, such as styrene, p-methylstyrene, alpha-methylstyrene andindene, among others, is well known. In a typical cationicpolymerization process a suitable unsaturated monomer is polymerized inthe presence of a cationic polymerization catalyst, an initiator, and anoptional Lewis base (in order to prevent initiation by proticimpurities), typically in an aprotic solvent under dry conditions at lowtemperature. The polymers formed in this method are living cationicpolymers (e.g., polymers in which the polymer chains typically continueto grow from the site of initiation until the monomer supply isexhausted, rather than terminating when the chain reaches a certainlength or when the catalyst is exhausted). The cationic polymerizationcatalyst may be, for example, a Lewis acid (e.g., BCl₃ or TiCl₄, amongothers). The initiator may be, for example, an alkyl halide or(haloalkyl)-aryl compound, for example, a monofunctional initiator suchas 2-chloro-2,4,4-trimethylpentane, a bifunctional initiator such as1,3-di(1-chloro-1-methylethyl)-5-(t-butyl)benzene, or a trifunctionalinitiator such as 1,3,5-tri(1-chloro-1-methylethyl)benzene, amongothers. Lewis bases include pyridine and its derivatives, such as2,6-ditert-butyl-pyridine (DTBP) or lutidine, among others.

As a specific example, a cationically polymerizable alkene such asisobutylene may be polymerized in the presence of a bifunctionalinitiator (e.g., 1,3-di(1-chloro-1-methylethyl)-5-(t-butyl)benzene,among others) followed by continued polymerization of a cationicallypolymerizable vinyl aromatic monomer such as styrene from the twopolyalkene chain ends, thereby forming a poly(vinylaromatic-b-alkene-b-vinyl aromatic) triblock copolymer (the presence ofthe initiator residue is typically ignored in block copolymerterminology as it is a minor component of the copolymer).

To render a poly(vinyl aromatic-b-alkene-b-vinyl aromatic) copolymersuch as SIBS more reactive, and thus better able to participate incrosslinking reactions, a small amount of a diene, for instance,isoprene or butadiene, may be added (e.g., admixed with the isobutyleneor added subsequent to the isobutylene) during the cationicpolymerization process, thereby yielding SIBS having unsaturation withinthe polyisobutylene blocks or at the ends thereof. Such a polymer canthen be crosslinked, for example, using techniques such as thosedescribed above for use in conjunction with EPDM rubber, among others.

As another example, block copolymers may be rendered more reactive byend-capping them with reactive compounds.

For instance, block copolymers may be end-capped with heterocycliccompounds, which may then be crosslinked by UV in the presence of aphotoinitiator. In this regard, U.S. Pat. No. 6,750,267 to Faust et al,which is hereby incorporated by reference, describes isobutylenepolymers, end-capped with heterocyclic compounds, which may be combinedwith a cationic photoinitiator (e.g., an onium salt selected fromdiaryliodonium salts of sulfonic acids, triarylsulfonium salts ofsulfonic acids, diaryliodonium salts of boronic acids, andtriarylsulfonium salts of boronic acids, among others) and exposed to anenergy source such as ultraviolet light or visible light in an amountsufficient to cure (i.e., crosslink) the composition.

Triblock copolymers for use in the present invention may be formed, forexample, by cationically polymerizing a first monomer (e.g.,isobutylene) from a bifunctional initiator (e.g.,1,3-di(1-chloro-1-methylethyl)-5-(t-butyl)benzene), followed by cationicpolymerization of a second monomer (e.g., styrene). The polymerizationis terminated prior to complete conversion of the styrene monomer. Thetriblock copolymer thus formed, for example,poly(styrene-b-isobutylene-b-styrene), may then be isolated/purified,followed by end-capping with a heterocyclic compound (e.g.,2,2-difurylpropane or thiophene, among others) via a process like thandescribed in Faust et al. The end-capped polymers may then be combinedwith cationic photoinitiator and crosslinked by exposure to energysource (e.g., ultraviolet light).

As another example, block polymers may be prepared, which have reactivegroups at one or more chain ends, along one or more chains, or acombination thereof.

As a specific example, U.S. Pat. No. 5,981,895, U.S. Pat. No. 6,051,657and U.S. Pat. No. 6,194,597, each to Faust et al. and herebyincorporated by reference, describe methods for preparingsilyl-functional living cationic polymers which can be coupled to oneanother to form a moisture-curable telechelic system. The methodsutilize a functional initiator for the polymerization process, followedby a coupling the chain ends together using a di-functional linkingagent to form a moisture curable polymer. More particularly, the methodsdescribed comprise reacting, in the presence of a Lewis acid, at leastone cationically polymerizable monomer with a functional initiator whichcomprises a typical cationic polymerization initiation group (e.g., ahalogen, alkoxy, acyloxy or hydroxyl group) and a silane group (e.g.,—SiX_(n)R_(3-n), wherein R is selected from alkyl groups having 1 to 10carbon atoms or aryl groups having 6 to 10 carbon atoms, X is halogen,and n is 1, 2 or 3), for instance,

among others. The resulting living polymer is then coupled using asuitable coupling agent, for example, a molecule having at least twofuran rings, for instance,

among others.

According to one embodiment, copolymers for use in the present inventionmay be prepared, for example, by polymerization of a first cationicallypolymerizable high Tg monomer (e.g., a vinyl aromatic monomers such asstyrene) from a silyl functional initiator, followed by polymerizationof a second low Tg monomer (e.g., an alkene such as isobutylene). Theresulting silyl functionalized diblock copolymer may then be coupled toitself with a suitable coupling agent, for example, a molecule having atleast two furan rings such as those described above, among others. Theresulting HLH triblock copolymer (this terminology ignores the presenceof the initiator and coupling group residues, as noted above) is thenreacted with an alcohol (e.g., methanol, ethanol, propanol, butanol,etc.), whereby the halogen groups on silicon atoms are replaced by analkoxy functionality that corresponds to the alcohol. The resultingalkoxysilyl-functional polymer may then be isolated from the reactionsolution by conventional means, such as precipitation with anon-solvent. Such polymers may be cured by exposure to moisture, andthey may optionally contain additional agents such as, for instance,catalysts (e.g., organo-tin catalysts such as tin(II)-2-ethylhexanoate,among others) and/or crosslinking agents.

Moisture curable polymers are also described in U.S. Pat. No. 6,469,115to Faust et al., which is hereby incorporated by reference, in whichcationic polymerization of an alkene, such as isobutylene, is conductedin the presence of a silyl functional initiator, for example, one ofthose described above. Moreover, a silyl-functional vinyl aromaticmonomer is also employed in the polymerization process such as,

where R″ is independently selected from alkyl groups having 1 to 10carbon atoms or aryl groups having 6 to 10 carbon atoms, R′″ is adivalent non-aromatic hydrocarbon group having 2 to 6 carbon atoms, X isa halogen group, and n is independently 1, 2 or 3, for example,2-dichlorolmethylsilyl-ethyl-styrene (DSiSt). In some embodiments, thealkene monomer is polymerized first, followed by polymerization of thesilyl-functional monomer after the alkene polymerization is essentiallycomplete. In other embodiments, the alkene monomer and silyl-functionalmonomer are polymerized simultaneously. In either case, as discussedabove, the resulting polymers is then reacted with an alcohol, and theresulting alkoxysilyl-functional polymer is isolated. Such polymers maybe crosslinked by exposure to moisture, optionally in the presence ofadditional agents such as, for instance, catalysts and/or crosslinkingagents.

Polymers for use in the present invention may be made using analogousprocedures. For instance, a silyl-functional initiator, for example, oneof those described above (which are mono-functional for purposes ofcationic polymerization) may be employed, with high Tg monomerpolymerization proceeding before low Tg monomer polymerization. Asilyl-functional vinyl monomer, for example, one of those describedabove may be introduced at one or more points in the process, forexample, introduced before the high Tg monomer, introduced admixed withthe high Tg monomer, introduced after the high Tg monomer and before thelow Tg monomer, introduced admixed with the low Tg monomer, introducedafter the low Tg monomer, as well as any combination of the foregoing.For example, styrene polymerization may proceed from thesilyl-functional initiator, followed by isobutylene polymerization,followed by polymerization of a silyl-functional vinyl aromatic monomer.As another example, styrene polymerization may proceed from asilyl-functional initiator, followed by polymerization of asilyl-functional vinyl aromatic monomer, followed by isobutylenepolymerization. Regardless of the embodiment, the resulting polymers maybe coupled to one another, for example, using a molecule having at leasttwo furan rings, for instance, bFPF, as described above. The resultingcoupled polymer may then be reacted with an alcohol, and the resultingalkoxysilyl-functional polymer isolated. Such polymers may becrosslinked by exposure to moisture, optionally in the presence ofadditional agents such as, for instance, catalysts and/or crosslinkingagents.

As another example, a difunctional initiator may be employed, with lowTg monomer polymerization proceeding before high Tg monomerpolymerization. A silyl-functional vinyl aromatic monomer like thosedescribed above may be introduced at one or more points in the process,for example, introduced before the low Tg monomer, introduced admixedwith the low Tg monomer, introduced after the low Tg monomer and beforethe high Tg monomer, introduced admixed with the high Tg monomer,introduced after the high Tg monomer, as well as any combination of theforegoing. As a first example, isobutylene polymerization may proceedfrom a difunctional initiator, followed by styrene polymerization,followed by polymerization of a silyl-functional vinyl aromatic monomer.As a second example, isobutylene polymerization may proceed from adifunctional initiator, followed by polymerization of a silyl-functionalvinyl aromatic monomer, followed by styrene polymerization. As a thirdexample, polymerization or a mixture of isobutylene and silyl-functionalvinyl aromatic monomer may proceed from a difunctional initiator,followed by polymerization styrene. Regardless of the embodiment, theresulting polymers may be reacted with an alcohol, isolated, andcrosslinked by exposure to moisture, optionally in the presence ofadditional agents such as, for instance, catalysts and/or crosslinkingagents, as described above.

Further moisture curable polymers are described in U.S. Pat. No.6,268,451 to Faust et al., which is hereby incorporated by reference, inwhich the following three monomers are simultaneously polymerized in thepresence of a Lewis acid and a solvent: (a) an alkene monomer, forexample, isobutylene, (b) a first silyl-functional vinyl aromatic thatis much more reactive than the alkene monomer, for example, avinylphenyl monomer such as

and (c) a second silyl-functional vinyl aromatic that is much lessreactive than the alkene monomer, for example, analpha-alkyl-substituted vinylphenyl monomer such as

where R and R′ are divalent non-aromatic hydrocarbon groups having 2 to6 carbon atoms, R″ is selected from alkyl groups having 1 to 10 carbonatoms or aryl groups having 6 to 10 carbon atoms, X is independently ahydrolyzable group such as a halogen group, and n is independently 1, 2or 3. The resulting polymer is said to be a “pseudo-telechelic”terpolymer, which denotes a copolymer having one type of reactivesilyl-functional unit statistically concentrated near the head of theterpolymer chain and a slightly different type of reactivesilyl-functional unit statistically concentrated at the tail of theterpolymer. Such polymers may be reacted with an alcohol, isolated, andcrosslinked by exposure to moisture as described above.

In certain embodiments of the invention, an interpenetrating polymernetwork (IPN) or a semi-IPN is created in which where a supplementalpolymer is crosslinked in the presence of a block copolymer thatcontains (a) at least one low Tg block and (b) at least one high Tgblock. Without wishing to be bound by theory, it is believed that bycrosslinking the supplemental polymer, the block copolymer is anchoredinto the crosslinked polymeric region through covalent crosslinks (ifthe block copolymer is reactive), chain entanglement, or both.

Examples of supplemental polymers may be selected from polymers thatcrosslink upon exposure to radiation, heat and/or a chemical agent suchas moisture. Specific examples of such polymers include homopolymer andcopolymers that contain alkene units, for example, olefin units such asethylene and/and propylene units, or diene units such as isoprene and/orbutadiene units, among others. As noted above, such polymers may becrosslinked, for example, upon exposure to energy or a chemical curingagent, optionally after having undergone chemical reaction to createreactive groups along the polymer backbone (e.g., alkoxysilane groups,anhydride groups, epoxy groups, etc.), optionally in the presence ofcatalysts (e.g., peroxides, photoinitiators, etc.) and/or optionally inthe presence of crosslinking agents (e.g., multifunctional species suchas those with vinyl, thiol, hydroxyl and/or amine groups, among others).Further specific examples include crosslinkable polymers which areformed using functional initiators (e.g., silyl functional initiators,among many others), functional monomers (e.g., silyl-functionalmonomers, among many others), and/or functional end-caps (e.g.,heterocyclic compounds, among many others). Further informationregarding these specific examples is discussed above, and is applicableto homopolymers and copolymers other than the block copolymersexemplified.

For example, a crosslinkable supplemental polymer, for instance, ahomopolymer such as polyethylene or polybutylene, or a copolymer such aspolyethylene-co-polybutylene or polyethylene-co-butylacrylate, may becrosslinked in the presence of (a) a triblock copolymer having areactive low Tg midblock and high Tg endblocks, for example, the SEBScopolymer, or (b) a triblock copolymer having a nonreactive low Tgmidblock and high Tg endblocks, for example, the SIBS copolymer.Optionally, crosslinking may proceed after generating reactive groupsalong the polymer backbone (e.g., alkoxysilane groups and anhydridegroups as discussed above, among others), in the presence of catalysts(e.g., peroxides and photoinitiators as discussed above, among others),and/or in the presence of crosslinking agents (e.g., multifunctionalspecies such as those with vinyl, hydroxyl or amine groups as discussedabove, among others). Without wishing to be bound by theory, it isbelieved that the SEBS becomes anchored into the crosslinked polymericregion through a combination of covalent crosslinks and chainentanglement, whereas the SIBS becomes anchored into the crosslinkedpolymeric region through chain entanglement.

In certain embodiments, one or more therapeutic agents are provided on,within or beneath the crosslinked polymeric regions in accordance withthe invention. “Therapeutic agents,” “drugs,” “pharmaceutically activeagents,” “pharmaceutically active materials,” and other related termsmay be used interchangeably herein.

Exemplary therapeutic agents for use in conjunction with the presentinvention include the following: (a) anti-thrombotic agents such asheparin, heparin derivatives, urokinase, and PPack (dextrophenylalanineproline arginine chloromethylketone); (b) anti-inflammatory agents suchas dexamethasone, prednisolone, corticosterone, budesonide, estrogen,sulfasalazine and mesalamine; (c)antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel,5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones,endostatin, angiostatin, angiopeptin, monoclonal antibodies capable ofblocking smooth muscle cell proliferation, and thymidine kinaseinhibitors; (d) anesthetic agents such as lidocaine, bupivacaine andropivacaine; (e) anti-coagulants such as D-Phe-Pro-Arg chloromethylketone, an RGD peptide-containing compound, heparin, hirudin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, aspirin, prostaglandininhibitors, platelet inhibitors and tick antiplatelet peptides; (f)vascular cell growth promoters such as growth factors, transcriptionalactivators, and translational promotors; (g) vascular cell growthinhibitors such as growth factor inhibitors, growth factor receptorantagonists, transcriptional repressors, translational repressors,replication inhibitors, inhibitory antibodies, antibodies directedagainst growth factors, bifunctional molecules consisting of a growthfactor and a cytotoxin, bifunctional molecules consisting of an antibodyand a cytotoxin; (h) protein kinase and tyrosine kinase inhibitors(e.g., tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs;(j) cholesterol-lowering agents; (k) angiopoietins; (l) antimicrobialagents such as triclosan, cephalosporins, aminoglycosides andnitrofurantoin; (m) cytotoxic agents, cytostatic agents and cellproliferation affectors; (n) vasodilating agents; (o) agents thatinterfere with endogenous vasoactive mechanisms; (p) inhibitors ofleukocyte recruitment, such as monoclonal antibodies; (q) cytokines; (r)hormones; (s) inhibitors of HSP 90 protein (i.e., Heat Shock Protein,which is a molecular chaperone or housekeeping protein and is needed forthe stability and function of other client proteins/signal transductionproteins responsible for growth and survival of cells) includinggeldanamycin, (t) alpha receptor antagonist (such as doxazosin,Tamsulosin) and beta receptor agonists (such as dobutamine, salmeterol),beta receptor antagonist (such as atenolol, metaprolol, butoxamine),angiotensin-II receptor antagonists (such as losartan, valsartan,irbesartan, candesartan and telmisartan), and antispasmodic drugs (suchas oxybutynin chloride, flavoxate, tolterodine, hyoscyamine sulfate,diclomine) (u) bARKct inhibitors, (v) phospholamban inhibitors, (w)Serca 2 gene/protein, (x) immune response modifiers includingaminoquizolines, for instance, imidazoquinolines such as resiquimod andimiquimod, and (y) human apolioproteins (e.g., AI, AII, AIII, AIV, AV,etc.).

Numerous therapeutic agents, not necessarily exclusive of those listedabove, have been identified as candidates for vascular treatmentregimens, for example, as agents targeting restenosis. Such agents areuseful for the practice of the present invention and include one or moreof the following: (a) Ca-channel blockers including benzothiazapinessuch as diltiazem and clentiazem, dihydropyridines such as nifedipine,amlodipine and nicardapine, and phenylalkylamines such as verapamil, (b)serotonin pathway modulators including: 5-HT antagonists such asketanserin and naftidrofuryl, as well as 5-HT uptake inhibitors such asfluoxetine, (c) cyclic nucleotide pathway agents includingphosphodiesterase inhibitors such as cilostazole and dipyridamole,adenylate/Guanylate cyclase stimulants such as forskolin, as well asadenosine analogs, (d) catecholamine modulators including α-antagonistssuch as prazosin and bunazosine, β-antagonists such as propranolol andα/β-antagonists such as labetalol and carvedilol, (e) endothelinreceptor antagonists, (f) nitric oxide donors/releasing moleculesincluding organic nitrates/nitrites such as nitroglycerin, isosorbidedinitrate and amyl nitrite, inorganic nitroso compounds such as sodiumnitroprusside, sydnonimines such as molsidomine and linsidomine,nonoates such as diazenium diolates and NO adducts of alkanediamines,S-nitroso compounds including low molecular weight compounds (e.g.,S-nitroso derivatives of captopril, glutathione and N-acetylpenicillamine) and high molecular weight compounds (e.g., S-nitrosoderivatives of proteins, peptides, oligosaccharides, polysaccharides,synthetic polymers/oligomers and natural polymers/oligomers), as well asC-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds andL-arginine, (g) ACE inhibitors such as cilazapril, fosinopril andenalapril, (h) ATII-receptor antagonists such as saralasin and losartin,(i) platelet adhesion inhibitors such as albumin and polyethylene oxide,(j) platelet aggregation inhibitors including cilostazole, aspirin andthienopyridine (ticlopidine, clopidogrel) and GP IIb/IIIa inhibitorssuch as abciximab, epitifibatide and tirofiban, (k) coagulation pathwaymodulators including heparinoids such as heparin, low molecular weightheparin, dextran sulfate and β-cyclodextrin tetradecasulfate, thrombininhibitors such as hirudin, hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone) and argatroban, FXa inhibitorssuch as antistatin and TAP (tick anticoagulant peptide), Vitamin Kinhibitors such as warfarin, as well as activated protein C, (l)cyclooxygenase pathway inhibitors such as aspirin, ibuprofen,flurbiprofen, indomethacin and sulfinpyrazone, (m) natural and syntheticcorticosteroids such as dexamethasone, prednisolone, methprednisoloneand hydrocortisone, (n) lipoxygenase pathway inhibitors such asnordihydroguairetic acid and caffeic acid, (o) leukotriene receptorantagonists, (p) antagonists of E- and P-selectins, (q) inhibitors ofVCAM-1 and ICAM-1 interactions, (r) prostaglandins and analogs thereofincluding prostaglandins such as PGE1 and PGI2 and prostacyclin analogssuch as ciprostene, epoprostenol, carbacyclin, iloprost and beraprost,(s) macrophage activation preventers including bisphosphonates, (t)HMG-CoA reductase inhibitors such as lovastatin, pravastatin,fluvastatin, simvastatin and cerivastatin, (u) fish oils andomega-3-fatty acids, (v) free-radical scavengers/antioxidants such asprobucol, vitamins C and E, ebselen, trans-retinoic acid and SOD mimics,(w) agents affecting various growth factors including FGF pathway agentssuch as bFGF antibodies and chimeric fusion proteins, PDGF receptorantagonists such as trapidil, IGF pathway agents including somatostatinanalogs such as angiopeptin and ocreotide, TGF-β pathway agents such aspolyanionic agents (heparin, fucoidin), decorin, and TGF-β antibodies,EGF pathway agents such as EGF antibodies, receptor antagonists andchimeric fusion proteins, TNF-α pathway agents such as thalidomide andanalogs thereof, Thromboxane A2 (TXA2) pathway modulators such assulotroban, vapiprost, dazoxiben and ridogrel, as well as proteintyrosine kinase inhibitors such as tyrphostin, genistein and quinoxalinederivatives, (x) MMP pathway inhibitors such as marimastat, ilomastatand metastat, (y) cell motility inhibitors such as cytochalasin B, (z)antiproliferative/antineoplastic agents including antimetabolites suchas purine analogs (e.g., 6-mercaptopurine or cladribine, which is achlorinated purine nucleoside analog), pyrimidine analogs (e.g.,cytarabine and 5-fluorouracil) and methotrexate, nitrogen mustards,alkyl sulfonates, ethylenimines, antibiotics (e.g., daunorubicin,doxorubicin), nitrosoureas, cisplatin, agents affecting microtubuledynamics (e.g., vinblastine, vincristine, colchicine, Epo D, paclitaxeland epothilone), caspase activators, proteasome inhibitors, angiogenesisinhibitors (e.g., endostatin, angiostatin and squalamine), rapamycin,cerivastatin, flavopiridol and suramin, (aa) matrixdeposition/organization pathway inhibitors such as halofuginone or otherquinazolinone derivatives and tranilast, (bb) endothelializationfacilitators such as VEGF and RGD peptide, and (cc) blood rheologymodulators such as pentoxifylline.

A wide range of therapeutic agent loadings can be used in conjunctionwith the medical devices of the present invention, with thetherapeutically effective amount being readily determined by those ofordinary skill in the art. Typical loadings range, for example, from 1wt % or less to 2 wt % to 5 wt % to 10 wt % to 25 wt % or more of thepolymeric mass.

Medical devices having sustained release profiles are beneficial incertain embodiments of the invention. By “sustained release profile” ismeant a release profile in which effective amounts of therapeutic agentsare released from the medical device to the host tissue or physiologicalenvironment over an extended period, such as days, weeks or even months.

Numerous techniques are available for forming polymeric regions inaccordance with the present invention. In general, the herein describedpolymeric regions are processed into a desired form prior to orsimultaneously with the formation of covalent crosslinks.

For example, where the polymeric region is formed from one or morepolymers having thermoplastic characteristics, a variety of standardthermoplastic processing techniques may be used to form the polymericregion. Using these techniques, a polymeric region can be formed, forinstance, by (a) first providing a melt that contains the polymer(s) andany supplemental agents such as catalyst(s), crosslinking agent(s),therapeutic agent(s), and so forth and (b) subsequently cooling themelt. Examples of thermoplastic processing techniques, includingcompression molding, injection molding, blow molding, spraying, vacuumforming and calendaring, extrusion into sheets, fibers, rods, tubes andother cross-sectional profiles of various lengths, and combinations ofthese processes. Using these and other thermoplastic processingtechniques, entire devices or portions thereof can be made.

Other processing techniques besides thermoplastic processing techniquesmay also be used to form the polymeric regions of the present invention,including solvent-based techniques. Using these techniques, a polymericregion can be formed, for instance, by (a) first providing a solution ordispersion that contains the polymer(s) and any supplemental agents suchas catalyst(s), crosslinking agent(s), therapeutic agent(s), and soforth and (b) subsequently removing the solvent. The solvent that isultimately selected will contain one or more solvent species, which aregenerally selected based on their ability to dissolve the polymer(s)that form the polymeric region (and in many embodiments the therapeuticagent(s) and supplemental agent, if any(s) as well), in addition toother factors, including drying rate, surface tension, etc. Preferredsolvent-based techniques include, but are not limited to, solventcasting techniques, spin coating techniques, web coating techniques,solvent spraying techniques, dipping techniques, techniques involvingcoating via mechanical suspension including air suspension, ink jettechniques, electrostatic techniques, and combinations of theseprocesses.

In some embodiments of the invention, a polymer containing solution(where solvent-based processing is employed) or a polymer melt (wherethermoplastic processing is employed) is applied to a substrate to forma polymeric region. For example, the substrate can correspond to all ora portion of an implantable or insertable medical device to which apolymeric coating is applied, for example, by spraying, extrusion, andso forth. The substrate can also be, for example, a template, such as amold, from which the polymeric region is removed after solidification.In a specific example, a load bearing joint is cast in this manner. Inother embodiments, for example, extrusion and co-extrusion techniques,one or more polymeric regions are formed without the aid of a substrate.In a specific example, an entire medical device is extruded. In another,a polymeric coating layer is co-extruded along with and underlyingmedical device body.

Crosslinking may be induced, for example, subsequent to such processes(e.g., by exposure to energy (e.g., heat, radiation, etc.), to achemical species (e.g., moisture), or to any other agent that results incrosslinking. Crosslinking may also be induced during the formingprocess in which case these processes are “reactive” processes. A commonexample is reactive extrusion, in which a material is thermally curedconcurrently with extrusion, among other examples.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

1. A medical device comprising a covalently crosslinked polymeric regionthat comprises at least one block copolymer, said block copolymercomprising a low Tg block selected from a polyalkene block comprisingisobutylene, a polyacrylate block and a polysiloxane block and a high Tgblock selected from a poly(vinyl aromatic) block, a polyacrylate block,and a polymethacrylate block, wherein molecules of said block copolymerare covalently crosslinked to themselves, to a supplemental polymer, orboth, and wherein said block copolymer further comprises a dienemonomer.
 2. The medical device of claim 1, comprising a plurality ofcrosslinked polymeric regions.
 3. The medical device of claim 1, whereinsaid block copolymer is a multiarm block copolymer comprising a low Tgmidblock and a plurality of high Tg end blocks.
 4. The medical device ofclaim 3, wherein said low Tg midblock is said polyalkene block and saidhigh Tg endblocks are poly(vinyl aromatic) blocks.
 5. The medical deviceof claim 4, wherein said polyvinyl aromatic blocks comprise an aromaticmonomer selected from styrene, styrene sulfonic acids and salts thereof,hydroxy styrenes, alkyl substituted styrenes, ether substitutedstyrenes, ester substituted styrenes, amino substituted styrenes, silylsubstituted styrenes, vinyl pyridines, alkyl substituted vinylpyridines, and combinations of the same.
 6. The medical device of claim1, wherein carbon atoms of said molecules of said block copolymer arecovalently bonded to one another.
 7. The medical device of claim 1,wherein said block copolymer is covalently crosslinked through amultifunctional crosslinking agent.
 8. The medical device of claim 7,wherein said multifunctional crosslinking agent comprises reactivegroups selected from unsaturated groups, amine groups, hydroxyl groups,thiol groups and combinations thereof.
 9. The medical device of claim 1,wherein said block copolymer is crosslinked through reactive groupspositioned along its length, at its ends, or both.
 10. The medicaldevice of claim 9, wherein said reactive groups are selected from silanegroups, anhydride groups, epoxy groups, and combinations of the same.11. The medical device of claim 9, wherein said reactive groups aresilane groups and wherein said polymeric region is crosslinked uponexposure to moisture.
 12. The medical device of claim 9, wherein saidreactive groups are anhydride groups and wherein said polymeric regionis crosslinked via a multifunctional crosslinking agent comprisingreactive species selected from amine groups, hydroxyl groups andcombinations thereof.
 13. The medical device of claim 1, wherein saidblock copolymer is crosslinked by exposure to a curing agent selectedfrom energy, chemical agents, and combinations thereof.
 14. The medicaldevice of claim 1, wherein said covalently crosslinked polymeric regioncomprises a covalently crosslinked supplemental polymer.
 15. The medicaldevice of claim 14, wherein molecules of said supplemental polymer arecovalently crosslinked to themselves, to said block copolymer, or both.16. The medical device of claim 1, wherein said polymeric regioncorresponds to an entire medical device or to an entire component of amedical device.
 17. The medical device of claim 1, wherein saidpolymeric region is in the form of a layer that at least partiallycovers an underlying substrate.
 18. The medical device of claim 1,wherein a therapeutic agent is provided on, within or beneath saidpolymeric region.
 19. The medical device of claim 18, wherein saidtherapeutic agent is selected from antiproliferative agents, vascularcell growth promoters, antimicrobial agents, analgesic agents,immune-suppression agents, antiinflammatory agents, antispasmodicagents, alpha blockers, calcium channel blockers, beta agonists,neoplatic agents, cytostatic agents, and combinations thereof.
 20. Themedical device of claim 1, wherein said medical device is selected fromjoint prostheses and devices that transit tissue.
 21. The medical deviceof claim 1, wherein said medical device is selected from knee joints,hip joints, spinal disks and nuclei, vascular grafts, artificialligaments, and belly bands.
 22. The medical device of claim 20, whereinsaid device that transits tissue is selected from needles, sutures,guidewires, catheters, balloons, and balloon catheters.
 23. A medicaldevice comprising a covalently crosslinked polymeric region thatcomprises at least one block copolymer, said block copolymer comprisinga low Tg block selected from homopolymer and copolymer blocks comprisingone or more of isobutylene, butyl acrylate, butyl methacrylate, andethylene oxide and a high Tg block selected from a polyvinyl aromaticblock comprising styrene sulfonic acids and salts thereof, andhomopolymer and copolymer blocks comprising one or more of methylmethacrylate, 2-hydroxyethyl methacrylate, and styrene.
 24. The medicaldevice of claim 23, wherein said block copolymer is crosslinked throughreactive groups positioned along its length, at its ends, or both, andwherein said reactive groups are selected from silane groups, anhydridegroups, epoxy groups, and combinations of the same.
 25. The medicaldevice of claim 24, wherein said reactive groups are silane groups andwherein said polymeric region is crosslinked upon exposure to moisture.26. The medical device of claim 24, wherein said reactive groups areanhydride groups and wherein said polymeric region is crosslinked via amultifunctional crosslinking agent comprising reactive species selectedfrom amine groups, hydroxyl groups and combinations thereof.
 27. Themedical device of claim 23, wherein molecules of said block copolymerare covalently crosslinked to themselves, to a supplemental polymer, orboth, and wherein said block copolymer further comprises a dienemonomer.
 28. The medical device of claim 1, wherein said block copolymercomprises said polyalkene block comprising isobutylene and wherein saidhigh Tg block is said poly(vinyl aromatic) block.
 29. The medical deviceof claim 28, wherein said poly(vinyl aromatic) block comprises styrene.